PROJECT ABSTRACT Rhinovirus (RV) infections are ubiquitous across age, gender, and ethnicity and are the most frequent reason for healthcare visits. In the majority of affected persons, the symptoms of RV infections are mild and self-limiting. In persons with chronic rhinosinusitis (CRS), however, RV infections are a major cause of CRS exacerbations and associated morbidity. Recently, we found that RV-C species are common in adults, and that RV-C infections result in greater sinonasal symptoms compared with the well-studied RV-A and RV-B species. We also determined that rs6967330, a genetic risk variant in the recently discovered RV-C Cadherin Related Family Member 3 (CDHR3) viral receptor, causes a two-fold increase in the odds for adult CRS. Although CRS is a heterogeneous disorder, transcriptome studies of surgical tissues have determined significant dysregulation of genes associated with chemokine/cytokine signaling and epithelial-mesenchymal transitions (EMT). The objective of this application is to (i) determine if subjects with CRS and the rs6967330 CDHR3 risk allele have a different molecular endotype in response to RV-C infections as compared with those with the more frequent wild-type allele and (ii) determine if adult CRS subjects with the rs6967330 allele are more likely to have CRS exacerbations with RV-C infections compared to RV-A and RV-B infections. We hypothesize that in vitro studies of air-liquid-interface (ALI) cultures with the rs6967330 CDHR3 risk allele will generate a molecular endotype characterized by (i) increased RV-C binding and replication, ii) increased cytokines/chemokines associated with types 1 and 2 immunity, and iii) differentially expressed genes (DEGs) and EMT pathways associated with airway remodeling compared to epithelia expressing the wild-type allele. Likewise, we hypothesize that our in vivo studies of CRS subjects with the rs6967330 allele will reveal an increased number of CRS exacerbations secondary to RV-C infections that are characterized by increased sinonasal symptoms, nasal cytokine production, and transcriptomic changes in airway remodeling after infection. There is a critical need to understand the molecular mechanisms that underlie the increased pathogenicity of RV-C infections in persons with the rs6967330 CDHR3 risk allele to inform the development of new targeted strategies to prevent and slow the progression of CRS.